Methods and reagents for extracorporeal immunomodulatory therapy

Abstract

The invention features methods for altering the immunomodulatory activity of compositions containing peripheral blood mononuclear cells. The methods include the steps of contacting PBMCs with an amount of an aziridino-containing compound effective to react with and modify the PBMC nucleic acid.

What is claimed is:  
     
         1 . A method for treating a patient having an immune dysfunction, said method comprising the steps of: 
 (a) treating peripheral blood mononuclear cells with an effective amount of an aziridino-containing compound; and    (b) administering said peripheral blood mononuclear cells to said patient.    
     
     
         2 . The method of  claim 1 , wherein said immune dysfunction is cutaneous T-cell lymphoma, graft versus host disease, allograft rejection following organ transplantation, systemic lupus erythematosus, systemic sclerosis, inflammatory bowel disease, or rheumatoid arthritis.  
     
     
         3 . The method of  claim 1  wherein said compound has the formula (II):  
       
         
           
           
               
               
           
         
       
       wherein each R 1  is a divalent hydrocarbon moiety containing between 2 and 4 carbon atoms, inclusive; each of R 2 , R 3 , R 4 , R 5 , and R 6  is, independently, H or a monovalent hydrocarbon moiety containing between 1 arid 4 carbon atoms; and n is an integer between 1 and 10, inclusive.  
     
     
         4 . The method of  claim 1 , wherein said compound is ethyleneimine dimer.  
     
     
         5 . The method of  claim 1 , wherein said compound is an ethyleneimine trimer.  
     
     
         6 . The method of  claim 1 , wherein said compound is an ethyleneimine tetramer.  
     
     
         7 . The method of  claim 1 , wherein said compound has the formula (III):  
       
         
           
           
               
               
           
         
       
       wherein each R 1  is a divalent hydrocarbon moiety containing between 2 and 4 carbon atoms, inclusive; each of R 2 , R 3 , R 4 , R 5 , B 6 , and R 7  is, independently, H or a monovalent hydrocarbon moiety containing between 1 and 4 carbon atoms; X is Cl or Br, Y is a pharmaceutically acceptable counter anion; W is valency of Y; and n is an integer between 1 and 10, inclusive.  
     
     
         8 . The method of  claim 1 , wherein said compound has the formula (IV);  
       
         
           
           
               
               
           
         
       
       wherein each R1 is a divalent hydrocarbon moiety containing between 2 and 4 carbon atoms, inclusive; each of R 2 , R 3 , R 4 , R 5 , B 6 , and R 7  is, independently, H or a monovalent hydrocarbon moiety containing between 1 and 4 carbon atoms; X is Cal or Br; Y is a pharmaceutically acceptable counter anion; W is valency of Y; and n is an integer between 1 and 10, inclusive.  
     
     
         9 . A method for treating a patient having an immune dysfunction, said method comprising the steps of: 
 (a) extracorporeally treating peripheral blood mononuclear cells from said patient with an effective amount of an aziridino-containing compound;    (b) separately said peripheral blood mononuclear cells from said aziridino-containing compound; and    (c) administering said peripheral blood mononuclear cells to said patient.    
     
     
         10 . A method for preventing graft-versus-host (GVH) disease in a patient, the method comprising the steps of: 
 (a) extracorporeally treating a blood composition with an effective amount of an aziridino-containing compound; and    (b) administering said treated blood cell population to said patient,    thereby preventing GVH disease in said patient.    
     
     
         11 . The method of  claim 10 , wherein said blood composition comprises peripheral blood mononuclear cells (PBMC).  
     
     
         12 . The method of  claim 10 , wherein said blood composition is a non-leukoreduced blood cell concentrate.  
     
     
         13 . The method of  claim 10 , wherein said blood composition is a heterologous blood cell population.  
     
     
         14 . The method of  claim 10 , wherein said method further separating said aziridino-containing compound from said treated blood cell composition prior to administering said treated blood composition to said patient.  
     
     
         15 . The method of  claim 14 , wherein at least 99% of said aziridino-containing compound is removed from said treated blood cell composition prior to administering said treated blood composition to said patient.  
     
     
         16 . The method of  claim 10 , wherein said compound has the formula (II):  
       
         
           
           
               
               
           
         
       
       wherein each R 1  is a divalent hydrocarbon moiety containing between 2 and 4 carbon atoms, inclusive; each of R 2 , R 3 , R 4 , R 5 , and R 6  is, independently, H or a monovalent hydrocarbon moiety containing between 1 arid 4 carbon atoms; and n is an integer between 1 and 10, inclusive.  
     
     
         17 . The method of  claim 10 , wherein said compound is an ethyleneimine dimer.  
     
     
         18 . The method of  claim 10 , wherein said compound is an ethyleneimine trimer.  
     
     
         19 . The method of  claim 10 , wherein said compound is an ethyleneimine tetramer.  
     
     
         20 . The method of  claim 10 , wherein said compound has the formula (III):  
       
         
           
           
               
               
           
         
       
       wherein each R 1  is a divalent hydrocarbon moiety containing between 2 and 4 carbon atoms, inclusive; each of R 2 , R 3 , R 4 , R 5 , B 6 , and R 7  is, independently, H or a monovalent hydrocarbon moiety containing between 1 and 4 carbon atoms; X is Cl or Br, Y is a pharmaceutically acceptable counter anion; W is valency of Y; and n is an integer between 1 and 10, inclusive.  
     
     
         21 . The method of  claim 10 , wherein said compound has the formula (IV);  
       
         
           
           
               
               
           
         
       
       wherein each R1 is a divalent hydrocarbon moiety containing between 2 and 4 carbon atoms, inclusive; each of R 2 , R 3 , R 4 , R 5 , B 6 , and R 7  is, independently, H or a monovalent hydrocarbon moiety containing between 1 and 4 carbon atoms; X is Cal or Br; Y is a pharmaceutically acceptable counter anion; W is valency of Y; and n is an integer between 1 and 10, inclusive.  
     
     
         22 . The method of  claim 10 , wherein said patient is a human.  
     
     
         23 . The method of  claim 10 , wherein said patient suffers from or is at risk for immune dysfunction.  
     
     
         24 . The method of  claim 22 , wherein said human patient suffers from or is at risk for immune dysfunction.  
     
     
         25 . A method for preventing graft-versus-host (GVH) disease in a patient, the method comprising the steps of: 
 (a) treating a heterologous blood composition with an effective amount of an ethylene oligomer compound;    (b) removing said ethylene oligomer from said heterologous treated blood composition; and    (c) administering said treated blood cell population to said patient,    thereby preventing GVH disease in said patient.    
     
     
         26 . The method of  claim 25 , wherein said patient is a human.  
     
     
         27 . The method of  claim 25 , wherein said compound is an ethyleneimine dimer.  
     
     
         28 . The method of  claim 25 , wherein said compound is an ethyleneimine trimer.  
     
     
         29 . The method of  claim 25 , wherein said compound is an ethyleneimine tetramer.  
     
     
         30 . A method for treating graft-versus-host (GVH) disease in a patient, the method comprising the steps of: 
 (a) treating a heterologous blood composition with an effective amount of an aziridino-containing compound; and    (b) administering said treated blood cell population to said patient,    thereby treating GVH disease in said patient.    
     
     
         31 . A method for preventing graft-versus-host (GVH) disease in a patient, the method comprising the steps of: 
 (a) treating a heterologous blood composition with an effective amount of an ethylene oligomer compound;    (b) removing said ethylene oligomer from said heterologous treated blood composition; and    (c) administering said treated blood cell population to said patient,    thereby preventing GVH disease in said patient.    
     
     
         32 . A method for preventing an alloantibody response in a patient, the method comprising the steps of: 
 (a) treating a heterologous blood composition with an effective amount of an aziridino-containing compound; and    (b) administering said treated blood cell population to said patient,    thereby preventing said alloantibody response in said patient.    
     
     
         33 . A method for functionally inactivating a leukocyte in a patient, the method comprising the steps of: 
 (a) treating a heterologous blood composition comprising a leukocyte with an effective amount of an aziridino-containing compound; and    (b) administering said treated blood cell population to said patient,    thereby inactivating said leukocyte in said patient.    
     
     
         34 . The method of  claim 33 , wherein said leukocyte renders does not proliferate following said treatment.  
     
     
         35 . A blood composition produced by treating a composition comprising peripheral blood mononuclear cells with a non-viricidal amount of an aziridino-containing compound. wherein said aziridino-containing compound is present in an amount sufficient to inhibit proliferation of said peripheral blood mononuclear cells.